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Abstract Hedgehog signaling mediates embryologic development of the central nervous system and other tissues and is frequently hijacked by neoplasia to facilitate uncontrolled cellular proliferation. Meningiomas, the most common primary brain tumor, exhibit Hedgehog signaling activation in 6.5% of cases, triggered by recurrent mutations in pathway mediators such as SMO. In this study, we find 35.6% of meningiomas that lack previously known drivers acquired various types of somatic structural variations affecting chromosomes 2q35 and 7q36.3. These cases exhibit ectopic expression of Hedgehog ligands, IHH and SHH, respectively, resulting in Hedgehog signaling activation. Recurrent tandem duplications involving IHH permit de novo chromatin interactions between super-enhancers within DIRC3 and a locus containing IHH. Our work expands the landscape of meningioma molecular drivers and demonstrates enhancer hijacking of Hedgehog ligands as a route to activate this pathway in neoplasia.

Abstract Purpose Radiotherapy is, with surgery, one of the main therapeutic treatment strategies for meningiomas. No prospective study has defined a consensus for the delineation of target volumes for meningioma radiotherapy. Therefore, target volume definition is mainly based on information from retrospective studies that include heterogeneous patient populations. The aim is to describe delineation guidelines for meningioma radiotherapy as an adjuvant or definitive treatment with intensity-modulated radiation therapy and stereotactic radiation therapy techniques. This guideline is based on a consensus endorsed by a multidisciplinary group of brain tumor experts, members of the Association of French-speaking Neuro-oncologists (ANOCEF). Materials and methods A 3-step procedure was used. First, the steering group carried out a comprehensive review to identify divergent issues on meningiomas target volume delineation. Second, an 84-item web-questionnaire has been developed to precisely define meningioma target volume delineation in the most common clinical situations. Third, experts members of the ANOCEF were requested to answer. The first two rounds were completed online. A third round was carried out by videoconference to allow experts to debate and discuss the remaining uncertain questions. All questions remained in a consensus. Results Limits of the target volume were defined using visible landmarks on computed tomography and magnetic resonance imaging, considering the pathways of tumor extension. The purpose was to develop clear and precise recommendations on meningiomas target volumes. Conclusion New recommendations for meningiomas delineation based on simple anatomic boundaries are proposed by the ANOCEF. Improvement in uniformity in target volume definition is expected.

Abstract Activation-induced cytidine deaminase, AICDA or AID, is a driver of somatic hypermutation and class-switch recombination in immunoglobulins. In addition, this deaminase belonging to the APOBEC family may have off-target effects genome-wide, but its effects at pan-cancer level are not well elucidated. Here, we used different pan-cancer datasets, totaling more than 50,000 samples analyzed by whole-genome, whole-exome, or targeted sequencing. AID mutations are present at pan-cancer level with higher frequency in hematological cancers and higher presence at transcriptionally active TAD domains. AID synergizes initial hotspot mutations by a second composite mutation. AID mutational load was found to be independently associated with a favorable outcome in immune-checkpoint inhibitors (ICI) treated patients across cancers after analyzing 2000 samples. Finally, we found that AID-related neoepitopes, resulting from mutations at more frequent hotspots if compared to other mutational signatures, enhance CXCL13/CCR5 expression, immunogenicity, and T-cell exhaustion, which may increase ICI sensitivity.

In drinking water production from groundwaters, biological rapid sand filters (RSFs) can be used for ammonium and manganese removal in aerobic conditions. However, in some boreholes, a start-up duration of several months is required to reach the required removal capacity, leading to significant water losses. Moreover, in specific industrial cases, no exogenous biomass under the form of backwash water or activated sludge can be added to accelerate the process, and different approaches are seldom considered in the literature. With the aim of saving water, start-up strategies coupling water temperature increase and substrate dosing were studied to accelerate the installation of biological activities in a pilot plant fed with borehole water. These set-ups enabled a substantial acceleration of nitrification but no improvement of manganese oxidation in the experimental conditions, although the experiments showed no clear negative influence of nitrification, through nitrite accumulation, on biological manganese oxidation. To further save energy and reduce water loss, outlet water recirculation at a rate of 75% during the start-up phase was validated. The proposed start-up strategy enabled the complete installation of active biofilms with a mean start-up time reduction of 36% and water use reduction of 84% compared to the reference natural conditions. HIGHLIGHTS The accelerated start-up strategy designed for the production of drinking water yielded up to 90% of water saved in the best tested configuration.; Temperature increase and substrate dosing have a better impact on nitrification than on manganese oxidation.; No clear negative interaction between nitrification and manganese oxidation was observed.;

This article reviews the state of knowledge on the mechanisms of deterioration of concrete by agricultural and agro-industrial effluents, notably breeding effluents and biowaste valorised in anaerobic digestion plants. The main physicochemical characteristics of agricultural effluents are first listed in terms of components that are aggressive for cementitious materials. Then, the main mechanisms of deterioration of the cementitious materials exposed to the effluents are presented, as highlighted by laboratory studies (synthetic effluents and / or models, specific experimental devices) or with real effluents. The paper also points out the scientific and technical advances needed to improve the durability of concrete in these environments.

BackgroundChildren with ependymoma may experience a relapse in up to 50% of cases depending on the extent of resection. Key biological events associated with recurrence are unknown.Methodology/principal findingsTo discover the biology behind the recurrence of ependymomas, we performed CGHarray and a dual-color gene expression microarray analysis of 17 tumors at diagnosis co-hybridized with the corresponding 27 first or subsequent relapses from the same patient. As treatment and location had only limited influence on specific gene expression changes at relapse, we established a common signature for relapse. Eighty-seven genes showed an absolute fold change ≥2 in at least 50% of relapses and were defined as the gene expression signature of ependymoma recurrence. The most frequently upregulated genes are involved in the kinetochore (ASPM, KIF11) or in neural development (CD133, Wnt and Notch pathways). Metallothionein (MT) genes were downregulated in up to 80% of the recurrences. Quantitative PCR for ASPM, KIF11 and MT3 plus immunohistochemistry for ASPM and MT3 confirmed the microarray results. Immunohistochemistry on an independent series of 24 tumor pairs at diagnosis and at relapse confirmed the decrease of MT3 expression at recurrence in 17/24 tumor pairs (p = 0.002). Conversely, ASPM expression was more frequently positive at relapse (87.5% vs 37.5%, p = 0.03). Loss or deletion of the MT genes cluster was never observed at relapse. Promoter sequencing after bisulfite treatment of DNA from primary tumors and recurrences as well as treatment of short-term ependymoma cells cultures with a demethylating agent showed that methylation was not involved in MT3 downregulation. However, in vitro treatment with a histone deacetylase inhibitor or zinc restored MT3 expression.Conclusions/significanceThe most frequent molecular events associated with ependymoma recurrence were over-expression of kinetochore proteins and down-regulation of metallothioneins. Metallothionein-3 expression is epigenetically controlled and can be restored in vitro by histone deacetylase inhibitors.

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Abstract Purpose  The aim of this report is to enlighten the role of an early diagnosis and treatment of haemophilia A during the management of an intracranial haemorrhage as well as to discuss the efficiency of a subdural transcoronal puncture compared to a craniectomy as surgical treatment of the haematoma. Background  Haemophilia A constitutes a well-known risk factor for intracranial bleeding. However, it has been rarely described as a cause of subdural haematoma in neonates. Management of subdural haematomas in haemophilic patients is still debated. Materials and methods  We report two cases of infants with subacute subdural haematoma. The first of them had a familial history of haemophilia A. In the second subject, the diagnosis was obtained during the etiological workup of an intracranial haematoma. Both infants were successfully treated with transcoronal puncture of the subacute component of the haematoma and factor VIII infusion. Conclusions  Transcranial punctures associated to infusion of factor VIII should be considered an alternative surgical option in the management of subdural haematomas in neonates with haemophilia A. [ABSTRACT FROM AUTHOR]